Three-Dimensional Analysis of Mitochondrial Crista Ultrastructure in a Patient with Leigh Syndrome by In Situ Cryoelectron Tomography
Stephanie E. Siegmund,
Robert Grassucci,
Stephen D. Carter,
Emanuele Barca,
Zachary J. Farino,
Martí Juanola-Falgarona,
Peijun Zhang,
Kurenai Tanji,
Michio Hirano,
Eric A. Schon,
Joachim Frank,
Zachary Freyberg
Affiliations
Stephanie E. Siegmund
Department of Cellular, Molecular and Biophysical Studies, Columbia University Medical Center, New York, NY 10032, USA
Robert Grassucci
Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA
Stephen D. Carter
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Emanuele Barca
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
Zachary J. Farino
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA
Martí Juanola-Falgarona
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
Peijun Zhang
Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Kurenai Tanji
Department of Cellular, Molecular and Biophysical Studies, Columbia University Medical Center, New York, NY 10032, USA; Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
Michio Hirano
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
Eric A. Schon
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA
Joachim Frank
Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA; Department of Biological Sciences, Columbia University, New York, NY 10032, USA
Zachary Freyberg
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Corresponding author
Summary: Mitochondrial diseases produce profound neurological dysfunction via mutations affecting mitochondrial energy production, including the relatively common Leigh syndrome (LS). We recently described an LS case caused by a pathogenic mutation in USMG5, encoding a small supernumerary subunit of mitochondrial ATP synthase. This protein is integral for ATP synthase dimerization, and patient fibroblasts revealed an almost total loss of ATP synthase dimers. Here, we utilize in situ cryoelectron tomography (cryo-ET) in a clinical case-control study of mitochondrial disease to directly study mitochondria within cultured fibroblasts from a patient with LS and a healthy human control subject. Through tomographic analysis of patient and control mitochondria, we find that loss of ATP synthase dimerization due to the pathogenic mutation causes profound disturbances of mitochondrial crista ultrastructure. Overall, this work supports the crucial role of ATP synthase in regulating crista architecture in the context of human disease. : Organizational Aspects of Cell Biology; Structural Biology; Resolution Techniques Subject Areas: Organizational Aspects of Cell Biology, Structural Biology, Resolution Techniques
